Allergic diseases represent a major burden to human health and well-being. However, the mechanisms whereby allergens induce the pathogenic Th2 immune responses remain largely unknown. Similarly, the mechanisms of induction of protective Th2 responses against multi-cellular parasites are poorly defined. Using a protease allergen papain as a model system, we have recently demonstrated that basophils play an essential role in allergen-induced Th2 responses, by functioning as antigen-presenting cells and as a source of Th2 polarizing cytokines. The goal of this proposal is to characterize the mechanism of action of protease allergens and to elucidate key features of basophils that enable their function as initiators of Th2 responses. We will investigate signaling pathways and transcription factors activated by protease allergens in basophils. We will examine the phenotype of allergen-activated basophils and compare it to the FceRI and IL-3 receptor activated basophils. We will examine how basophil activation is negatively regulated by a variety of anti-inflammatory and immunoregulatory signals. Finally, we will investigate the mechanisms of basophil recruitment to the lymph nodes in response to allergen challenge. These studies should provide important insights into very important but poorly understood mechanisms of allergenicity and the function of basophils in allergic responses. PUBLIC HEALTH RELEVANCE: Despite the tremendous progress in understanding the mechanisms of induction of host defense from infection, there is almost nothing known about how allergens trigger the pathogenic type2 immune responses. We recently found that a poorly characterize cell type called basophil, play a key role in initiating Th2 immune responses following challenge with an allergen. In this application we propose to investigate the mechanism of basophil activation by protease allergens and to provide new insights into basophil function in initiating Th2 immune responses.